Catalytic asymmetric total syntheses of sesquiterpenoids, (+)- and (?)-ar-macrocarpene

Article abstract of DOI:10.1016/j.tet.2019.130918

Concise catalytic asymmetric total syntheses of aromatic sesquiterpenes, naturally occurring (+)-ar-macrocarpene (1) and unnatural (?)-ar-macrocarpene (ent-1) have been featured (6 steps, ～60–61% overall yields) from commercially available 4,4-dimethylcyc

Full text of DOI:10.1016/j.tet.2019.130918

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Catalytic asymmetric total syntheses of sesquiterpenoids, (+)- and (−)-ar-
macrocarpene
Arindam Khatua, Avishek Roy, Vishnumaya Bisai
PII:
S0040-4020(19)31337-7
https://doi.org/10.1016/j.tet.2019.130918
TET 130918
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 November 2019
Revised Date: 24 December 2019
Accepted Date: 27 December 2019
Please cite this article as: Khatua A, Roy A, Bisai V, Catalytic asymmetric total syntheses of
sesquiterpenoids, (+)- and (−)-ar-macrocarpene, Tetrahedron (2020), doi: https://doi.org/10.1016/
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Catalytic Asymmetric Total Syntheses of Sesquiterpenoids, (+)- and ()-ar-
Macrocarpene
Arindam Khatua, Avishek Roy, and Vishnumaya Bisai*

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Catalytic Asymmetric Total Syntheses of Sesquiterpenoids, (+)- and (
−)-ar-
Macrocarpene
Arindam Khatua, Avishek Roy, and Vishnumaya Bisai*

1
Tetrahedron
journal homepage: www.elsevier.com
Catalytic Asymmetric Total Syntheses of Sesquiterpenoids, (+)- and (
Macrocarpene
−)-ar-
Arindam Khatua,a Avishek Roy,a and Vishnumaya Bisai*a-c
aDepartment of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhauri, Bhopal - 462 066, Madhya Pradesh, India
bDepartment of Chemistry, Indian Institute of Science Education and Research Berhampur, Berhampur – 760 010, Odisha, India
cDepartment of Chemistry, Indian Institute of Science Education and Research Tirupati, Mangalam, Tirupati – 517 507, Andhra Pradesh, India
Contact: +91-755-269-1328, Fax: +91-755-269-2392. Address for correspondence: vishnumayabisai@gmail.com
*This work is dedicated respectfully to Professor H. Ila, JNCASR Bangalore on the occasion of her 70th birthday.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Concise catalytic asymmetric total syntheses of aromatic sesquiterpenes, naturally
occurring (+)-ar-macrocarpene (1) and unnatural (−)-ar-macrocarpene (ent-1) have been
featured (6 steps, ~60-61% overall yields) from commercially available 4,4-
dimethylcyclohex-2-enone 16. The enantioenriched allyl alcohol 12 is obtained from
catalytic enantioselective reduction of enone 13b using Corey-Bakshi-Shibata catalyst in
93% ee, which is found to be the key intermediate. A highly diastereoselective
hydrogenation of enantioenriched allyl alcohol 12 (10.3:1 dr) followed by deoxygenation
completes straightforward access to (+)-ar-macrocarpene (1) and (−)-ar-macrocarpene
(ent-1).
Available online
Keywords:
Enantioselective reactions, Corey-Bakshi-
Shibata (CBS) reduction, diastereoselective
hydrogenation, (+)-ar-macrocarpene (1), (−)-
ar-macrocarpene (ent-1)
2012 Elsevier Ltd. All rights reserved.
INTRODUCTION
Sesquiterpenoids display diverse commercial applications in the
pharmaceutical and perfumery industries together with their roles in
interactions of plants with other organisms (e.g., allelochemicals and
insecticides). However, still most of these terpenoids are purified
from plant sources and for majority of these compounds, their
biosynthetic pathways remain unknown.1 In recent years, huge
global interest in the synthesis of such hydrocarbons and their
oxygenated derivatives is further flushed in, owing to their volatile
and combustible properties which make them ideal candidates for
terpene-based renewable biofuels.1 Macrocarpenes (1-2) including
one such group of naturally occurring irregular sesquiterpenes
possessing a 3,3,4’-trimethyl-1,1’-(bicyclohexyl) skeleton seem to be
biogenetically derived from rearrangement of structural scaffold.
Notably, these sesquiterpenes bear only three terminal carbons and
the presence of the fourth terminal carbon might be incorporated
during the biogenesis of the dimethylcyclohexane ring. These
sesquiterpenoids were identified in foliage of Cupressus macrocarpa
by Cool in 2005 in widely varying amount.2
Figure 1: Sesquiterpenes sharing 3,3-gem-dimethyl 1-
arylcyclohexane, ar-macrocarpene (1), β-macrocarpene (2),
majapolene B (3), and acetylmajapolene B (4).
Other
structurally
correlated
sesquiterpenoids,3-4
include
Despite its limited natural range (only on Point Lobos and Cypress
Point, Monterey Co., California), Cupressus macrocarpa Hartw. ex
Gord. (Monterey cypress) is one of the most widely planted conifers
in the state. The minor component of N-hexane extract of this species
contains ar-macrocarpene 1 (Figure 1). The absolute configuration of
ar-macrocarpene 1 has been assigned tentatively, on the basis of the
optical rotation and correlation with the related natural products in
the literature.2
laurokamurenes B (5) and C (6), cuparane (7), cuparenic acid (8),
aplysin (9) and debromoaplysin (10) having same total numbers of
carbons i.e. they are structural isomers with rearranged structural
scaffolds (Figure 2). Apart from this, Majapolene B (3) (Figure 1),5 a
brominated sesquiterpene,6-7 was originally isolated from Laurencia
majuscula. Reisolation of majapolene B (3) from Laurencia sp.
(Teluk Juara, Malaysia), along with the isolation of the previously
unreported acetylmajapolene
B (4) (Figure 1), led to the

2
Tetrahedron
determination of the absolute configuration of both compounds by
(CBS) catalyst.13 Substituted enone 13b could be easily made by
vibrational circular dichroism (VCD).
Suzuki coupling of 2-iodoenone 14 with p-tolylboronic acid (Scheme
2). It was also envisioned that a racemic synthesis of (±)-ar-
macrocarpene (1) can be achieved just by reduction of 4,4-dimethyl
2-(p-tolyl) cyclohexanone 15 (Scheme 1).
Structurally, ar-macrocarpene (1)2 share a p-toylcyclohexane with a
gem-dimethyl group at the 3-position of cyclohexane ring (Figure 1),
whereas majapolene B (3) and acetylmajapolene B (4) share a
brominated p-(hydroxymethyl)cyclohexane scaffold (Figure 1).5 ar-
Macrocarpene (1) is a structural isomer of other naturally occurring
sesquiterpenoids such as laurokamurenes B-C (5-6),8 cuparanes (7-
8)9 and lauranes10 [such as aplysins (9-10)] sharing cyclopentanes
with three methyl groups (Figure 2). These three methyl groups are
situated on the 1-arylcyclopentane (particularly p-toylcyclohexane)
ring in 2,2,3-fashion,8 1,2,2-fashion,9 and 1,2,3-fashion.10 in
secondary metabolites 5-6, 7-8 and 9-10, respectively.
Scheme 1: Retrosynthetic analysis of (+)-ar-macrocarpene (1).
RESULTS AND DISCUSSIONS
Assuming above hypothesis, commercially available 4,4-
dimethylcyclohex-2-enone 16 was reacted with iodine in the
presence of potassium carbonate and 4-N,N-dimethyl aminopyridine
(DMAP) to afford 4,4-dimethyl 2-iodocyclohex-2-enone 1415 in 90%
yield (Scheme 2).
Figure
2:
Sesquiterpenes
sharing
1-arylcyclopentane,
laurokamurenes B and C (5-6), cuparanes (7-8), and aplysins (9-10).
Scheme 2. Synthesis of 4,4-dimethyl 2-iodocyclohexen-2-one 14.
Although macrocarpenes were isolated more than a decade ago, till
date just a single racemic approach of ar-macrocarpene 1 is featured
in the literature by Srikrishna and co-workers in 2007.11 They
reported the first total synthesis of (±)-ar-macrocarpene 1 starting
from 3-methylcyclohexenone in four steps. Therefore, there is an
urgent need for asymmetric synthesis of ar-macrocarpene 1 sharing
3,3-dimethyl 1-arylcyclohexane (Figure 1).
The iodoenone 14 was thereafter allowed to establish the reaction
condition for Suzuki coupling reaction using aryl boronic acid (Table
1). Following a quick optimization, it was found that 1equiv. of
iodoenone 14 could react with 1.5 equiv. of phenylboronic acid in
the presence of Na2CO3 in THF/H2O mixture at 70 ºC to afford
expected product 13a16 in up to 95% yield (entries 1-4) (Table 1).
RETROSYNTHETIC ANALYSIS
Table 1. Optimization of Suzuki coupling of iodoenone 14.
Recently, our group has shown first total synthesis of (+)-ar-
macrocarpene (1) following a key allylic diazene rearrangement
(ADR).12 Herein, we report unified catalytic enantioselective total
syntheses of naturally occurring (+)-ar-macrocarpene (1) as well as
unnatural antipode, (−)-ar-macrocarpene (ent-1) via
enantioselective reduction of enone using Corey-Bakshi-Shibata
(CBS) catalyst13 followed by
highly diastereoselective
hydrogenation. A racemic synthesis of (±)-ar-macrocarpene 1 is also
shown by a one-step reduction of carbonyl functionality under
Wolff-Kishner reduction conditions.14
a
key
a
S.
No. acid
equiv.
boronic
base
solvent
temp.
Ti
me
yield
1.
2.
3.
4.
1.2 equiv.
1.2 equiv.
1.5 equiv.
1.5 equiv.
K2CO3
K2CO3
Na2CO3
Cs2CO3
THF: H2O
DMF: H2O
THF: H2O
THF: H2O
70 ºC
70 ºC
70 ºC
70 ºC
8 h
9 h
8 h
8 h
89%
78%
95%
90%
Retrosynthetically, we imagined that enantioenriched 2-
arylcyclohexanol 11 may serve as advanced intermediate for
asymmetric synthesis (+)-ar-macrocarpene (1) via reductive cleavage
of the corresponding xanthate intermediate, which in turn could be
accessed from a highly diastereoselective reduction of allylalcohol
12 (Scheme 2). Allylalcohol 12 could be accessed through a key
enantioselective reduction of enone 13b using Corey-Bakshi-Shibata
aReactions were carried out on a 0.2 mmol of 14 with 0.3 mmol of
phenylboronic acid in organic solvent and water (1:1 ratio). bIsolated yields
after column chromatography.

3
Further, a variety of aryl boronic acids were tested under standard
Suzuki condition and the results are summarized in Figure 2. A
variety of 4,4-dimethyl 2-aryl cyclohex-2-eneones 13a-i were
synthesized from 4,4-dimethyl 2-iodocyclohex-2-ene 14 in good to
excellent yields (Figure 3).
Scheme 4. Diastereoselective hydrogenation of allylalcohol (±)-12.
Later, for asymmetric total synthesis of naturally occurring (+)-ar-
macrocarpene (1) further investigation on a CBS reduction of
sterically congested enone 13b was carried out (Scheme 5). A gem-
dimethyl group on cyclohexen-2-one always poses challenge and
influences the enantioselective outcome of these catalytic processes.
In this regard, effort towards a catalytic enantioselective reduction of
4,4-dimethyl-3-(p-tolyl)-2-cyclohexenone 13b under Corey-Bakshi-
Shibata reduction condition afforded allylic alcohol (−)-12 in 87%
yield with excellent enantioselectivity (93% ee) using (S)-CBS
reagent.18
aReactions were carried out on a 0.2 mmol of 14 with 0.3 mmol of aryl
boronic acid in THF and water (1:1 ratio). bIsolated yields after column
chromatography.
Figure 3. Substrate scope of Suzuki coupling reaction of 14.
Scheme 5. Catalytic enantioselective reduction of enone 13b .
Later, as per our hypothesis, one of the products i.e. compound 13b
was hydrogenated to furnish 4,4-dimethyl 2-aryl cyclohexanone 15
in 99% yield (Scheme 3). Wolff-Kishner reduction14 of compound
15 using hydrazine hydrate completed total synthesis of (±)-ar-
macrocarpene 1 (Scheme 3).
A plausible transition state for catalytic reduction of 2-(p-tolyl) 2-
cyclohexenone 13b using (S)-CBS reagent has been shown in Figure
4. As can be seen, in the favored transition state (I), large group
occupy pseudoequitorial position and small group occupy
pseudoaxial position in the 6-membered transition state leading to
the favourable interactions. In this favoured TS, ‘Si-face’ approach
of hydride leading to (R)-stereochemistry of allylalcohol 12,
whereas, ‘Re-face’ approach of hydride is retarded. In the disfavored
transition state II, if large group of cyclohexenone 13b occupy
pseudoaxial position.
Next, enantioenriched allylalcohol was hydrogenated under 1 atm.
pressure of hydrogen to furnish advanced intermediate 2-
arylcyclohexanol (−)-11 in quantitative yield with 10.3:1 dr.17 At this
stage what is left was to remove hydroxyl functionality to complete
total synthesis of (−)-ar-macrocarpene (ent-1). To achieve this, the
hydroxyl functionality in compound (−)-11 was converted to
xanthate (−)-17 in 93% yield (Scheme 5) and was reductively
cleaved with n-tributyltin hydride in the presence of catalytic AIBN
to afford (+)-ar-macrocarpene (1) in 90% yield (Scheme 6).19
Therefore, our efforts culminated in the total synthesis of naturally
occurring aromatic sesquiterpenes (+)-ar-macrocarpene (1) in 61%
overall yield over 6 steps from commercially available 4,4-
dimethylcyclohex-2-enone 16.
Scheme 3. Total synthesis of (±)-ar-macrocarpene (1).
In another sequence, Luche reduction17 of compound 13b afforded
allylalcohol 12 in 91% yields. Delightfully, subsequent
hydrogenation of 12 afforded 2-arylcyclohexanol (±)-11 in
quantitative yield with 10.3:1 dr, where major diastereomer was
found to be syn-stereochemistry (Scheme 4).18 The syn-
stereochemistry of (±)-11 was confirmed by nOe experiment and
COSY experiment (see Supporting Information for details).

4
Tetrahedron
Scheme 7. Total synthesis of unnatural (−)-ar-macrocarpene (ent-1).
CONCLUSIONS
In summary, we have developed concise total synthesis of
naturally occurring aromatic sesquiterpenes, (+)-ar-macrocarpene
(1) and unnatural (−)-ar-macrocarpene (ent-1) in 6 steps in ~60-
61% overall yield from commercially available 4,4-
dimethylcyclohex-2-enone. The key strategy of this approach (86%
ee)19 is enantioselective reduction of 4,4-dimethyl 2-aryl cyclohex-2-
Figure 4. Plausible transition states of enone reduction using (S)-
CBS.
enone 13b using (S)-CBS reagent followed by
a highly
diastereoselective hydrogenation to relay the stereochemistry
required for ar-macrocarpene.20 Further rationale extension of this
strategy for the synthesis of other naturally occurring
sesquiterpenoids is currently under active investigation in our
laboratory.
Me
Pd-C, H2 (1 atm.)
Me
OH
OH
NaH, THF
MeOH, 25 C, 1 h
CS2, MeI, 25 C, 6 h
H
99%
dr =10.3:1
93%
Me Me
Me Me
12
( )-
11
( )-
SUPPLEMENTARY MATERIALS
SMe
Me
Me
Supplementary data associated with this article can be found, in the
online version, at http:.....................
S
O
AIBN, nBu3SnH
C6H6, 80 °C, 6 h
H
H
90%
Materials.
Me Me
( )-ar-macrocarpene ( )
Me Me
17
( )-
Unless otherwise stated, reactions were performed in oven-dried
glassware fitted with rubber septa under an inert atmosphere and
were stirred with Teflon-coated magnetic stirring bars. Liquid
reagents and solvents were transferred via syringe using standard
Schlenk techniques. Tetrahydrofuran (THF) and diethyl ether (Et2O)
were distilled over sodium/benzophenone ketyl. Dichloromethane
(CH2Cl2), toluene, and benzene were distilled over calcium hydride.
All other solvents and reagents were used as received unless
otherwise noted. Reaction temperatures above 23 °C refer to oil bath
temperature. Thin layer chromatography was performed using silica
gel 60 F-254 precoated plates (0.25 mm) and visualized by UV
irradiation, anisaldehyde stain and other stains. Silica gel of particle
size 100-200 mesh was used for flash chromatography. Melting
points were recorded on a digital melting point apparatus and are
1
Scheme 6. Total synthesis of naturally occurring (+)-ar-
macrocarpene (1).
After successful completion total synthesis of (+)-ar-
macrocarpene (1), we shifted our attention for the synthesis of
unnatural analogue i.e. (−)-ar-macrocarpene (ent-1). Towards this
direction, catalytic reduction of 2-(p-tolyl) 2-cyclohexenone 13b was
performed under standard condition using other antipode of catalyst
i.e. (R)-CBS reagent. This reaction afforded product (+)-12 in 90%
isolated yield with 93% enantioselectivity (Scheme 7). After that,
following similar reaction sequence as shown in Scheme 6, we have
completed first catalytic asymmetric total synthesis of unnatural (−)-
ar-macrocarpene (ent-1).
1
uncorrected. H and 13C NMR spectra were recorded 400, 500 MHz
spectrometers with 13C operating frequencies of 100, 125 MHz
respectively. Chemical shifts (δ) are reported in ppm relative to the
1
residual solvent (CDCl3) signal (δ = 7.26 for H NMR and δ = 77.0
1
for 13C NMR). Data for H NMR spectra are reported as follows:
chemical shift (multiplicity, coupling constants, and number of
hydrogen). Abbreviations are as follows: s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), br (broad). IR spectra were

5
EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ = 7.40 – 7.30 (m,
recorded on a FT-IR system (Spectrum BX) and are reported in
frequency of absorption (cm-1). Only selected IR absorbencies are
reported. High-Resolution Mass Spectrometry (HRMS) and Low-
Resolution Mass Spectrometry (LRMS) data were recorded on
MicrOTOF-Q-II mass spectrometer using methanol as solvent.
5H), 6.73 (s, 1H), 2.65 (dd, J=7.4, 6.2, 2H), 2.02 – 1.96 (m, 2H), 1.28 (s,
6H); 13CNMR (100 MHz, CDCl3) δ = 197.8, 157.3, 137.3, 136.4, 128.7,
128.0, 127.6, 36.0, 35.3, 33.5, 28.0; IR (film)υmax: 2960, 2854, 2033,
1688, 1374, 1117, 1039, 872, 835 cm-1; HRMS (ESI-TOF) m/z: [M+H]+
calcd for C14H17O : 201.1264, found: 201.1259 (For literature reference
of compound 13a, see; DeNinno, M. P. J. Am. Chem. Soc. 1995, 117,
9927).
Synthesis of iodoenone 14:
In an oven-dried round-bottom flask compound 16 (0.5 mL, 3.80 mmol,
1.0 eq.) was taken in 12 mL of THF and H2O mixture (1:1) and K2CO3
(630 mg, 4.561 mmol, 1.2 eq.) was added. The reaction mixture was
stirred at 0 ºC for 10 min and then 4-N,N-dimethylaminopyridine
(DMAP) (92.8 mg, 0.76 mmol, 0.2 eq) and I2 (1.44 gm, 5.7 mmol, 1.5
eq) were added successively and stirred at rt. After completion of the
reaction (as judged by running TLC; 3 h), excess I2 was quenched with
saturated solution of sodium thiosulfate (10 mL) and extracted with ethyl
acetate (15 mL X 2 times). All the organic volatiles were dried with
anhydrous sodium sulphate and evaporated under reduced pressure.
Finally, the crude products were purified by flash chromatography using
(90:10 hexanes: EtOAc) to afford product 14.
4',5,5-Trimethyl-4,5-dihydro-[1,1'-biphenyl]-2(3H)-one
According to general procedure, compound 13b was obtained as yellow
(13b):
gel (0.88 mmol scale of reaction, 173.6 mg of product, 92% yield); Rf =
1
0.57 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ = 7.23 (d,
J=8.1, 2H), 7.18 (d, J=8.0, 2H), 6.70 (d, J=1.1, 1H), 2.68 – 2.61 (m, 2H),
2.38 (s, 3H), 2.01 – 1.95 (m, 2H), 1.27 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ = 198.0, 156.7, 137.3, 137.2, 133.5, 128.7, 128.6, 36.1, 35.3,
33.5, 28.1, 21.2; IR (film) υmax: 3031, 2967, 2835, 2060, 1682, 1261,
1039, 934, 864, 786 cm-1; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for
C15H18ONa : 237.1247, found: 237.1250.
3',5,5-Trimethyl-4,5-dihydro-[1,1'-biphenyl]-2(3H)-one(13c):
According to general procedure, compound 13c was obtained as yellow
oil (0.22 mmol scale of reaction, 41.9 mg of product, 89% yield); Rf =
2-Iodo-4,4-dimethylcyclohex-2-en-1-one (14): Compound 14 was
obtained as yellow gel (855 mg, 90% yield); Rf = 0.50 (20% EtOAc in
hexane); 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 2.77 – 2.62 (m,
2H), 2.05 – 1.87 (m, 2H), 1.22 (s, 6H); 13CNMR (100 MHz, CDCl3) δ
192.0, 168.0, 101.8, 38.0, 36.0, 33.3, 27.4 (For literature reference of
compound 14, see; Takahashi, A.; Ogura, Y.; Enomoto, M.; Kuwahara,
S. Tetrahedron 2016, 72, 6634).
1
0.58 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 7.35 – 7.33
(m, 1H), 7.33 – 7.30 (m, 1H), 7.28 (d, J = 7.3 Hz, 1H), 7.24 – 7.19 (m,
1H), 6.41 (t, J = 1.5 Hz, 1H), 2.63 (d, J = 1.7 Hz, 2H), 2.38 (s, 3H), 2.33
(s, 2H), 1.12 (s, 6H); 13C NMR (100 MHz, CDCl3) δ = 200.3, 158.1,
139.0, 138.4, 130.8, 128.7, 126.8, 124.2, 123.3, 50.9, 42.4, 33.7, 28.4,
21.5; IR (film) υmax: 3013, 2864, 2055, 1695, 1167, 1122, 867, 760 cm-1;
HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C15H18ONa : 237.1250,
found: 237.1247.
General procedure for the synthesis of 13a-i via Suzuki coupling:
In an oven-dried round-bottm flask, under N2 atmosphere, 2-iodo-
cyclohexenone 14 (0.22 mmol, 1 equiv.) was taken in THF (3 mL) and
2(M) Na2CO3 solution (3 mL) and the reaction mixture was degassed for
5 mins to make it oxygen-free. To this solution arylboronic acid (0.33
mmol, 1.5 equiv.) was added followed by the addition of 5 mol%
Pd(PPh3)4. Then the reaction mixture was kept in a preheated oil bath at
70 ºC and stirring was continued for 8 h. After completion of the reaction
(as judged by running TLC), the reaction mixture was extracted with
ethyl acetate (10 mL X 2). The crude material was purified through
column chromatography by using ethyl acetate and petroleum ether as
eluents.
4'-Methoxy-5,5-Dimethyl-4,5-dihydro-[1,1'-biphenyl]-2(3H)-one
(13d): According to general procedure, compound 13d was obtained as
colorless oil (0.22 mmol scale of reaction, 47.1 mg of product, 93%
1
yield); Rf = 0.52 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ
7.34 – 7.28 (m, 1H), 7.16 (dd, J = 7.5, 1.8 Hz, 1H), 6.97 – 6.88 (m, 2H),
6.16 (t, J = 1.6 Hz, 1H), 3.80 (s, 3H), 2.61 (d, J = 1.8 Hz, 2H), 2.31 (s,
2H), 1.10 (s, 6H); 13C NMR (100 MHz, CDCl3) δ: 198.1, 156.5, 148.3,
136.8, 129.2, 121.0, 110.8, 55.9, 36.0, 35.4, 33.5, 28.1; IR (film) υmax
:
3081, 2937, 2167, 1686, 1411, 1237, 1209, 1026, 943, 862, 746 cm-1;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H19O2 : 231.1380, found:
257.1371.
5,5-Dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4H)-one (13a): According
to general procedure, compound 13a was obtained as colorless gel (0.22
mmol scale of reaction, 41.8 mg of product, 95% yield); Rf = 0.55 (20%

6
Tetrahedron
3'-Methoxy-5,5-dimethyl-4,5-dihydro-[1,1'-biphenyl]-2(3H)-one
(13e): According to general procedure, compound 13e was obtained as
yellow oil (0.22 mmol scale of reaction, 44.0 mg of product, 87% yield);
1
Rf = 0.55 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ: 7.36
– 7.28 (m, 1H), 7.16 (dd, J = 7.5, 1.8 Hz, 1H), 6.98 – 6.87 (m, 2H), 6.16
(t, J = 1.6 Hz, 1H), 3.80 (s, 3H), 2.61 (d, J = 1.8 Hz, 2H), 2.31 (s, 2H),
1.10 (s, 6H); 13C NMR (100 MHz, CDCl3) δ: 198.1, 156.5, 148.7, 148.3,
136.8, 129.2, 121.0, 112.2, 110.8, 55.9, 36.0, 35.4, 33.5, 28.1; IR (film)
υmax: 2962, 2834, 2261, 1958, 1636, 1325, 1167, 1075, 967, 867, 776 cm-
1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H19O2 : 231.1380, found:
231.1369.
4'-(Hydroxymethyl)-5,5-Dimethyl-4,5-dihydro-[1,1'-biphenyl]-2(3H)-
one (13i): According to general procedure, compound 13i was obtained
as yellow gel (0.22 mmol scale of reaction, 43.5 mg of product, 86%
1
yield); Rf = 0.28 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3)
δ: 7.70 – 7.57 (m, 2H), 7.48 (dd, J = 7.4, 1.4 Hz, 2H), 6.46 (d, J = 0.9
Hz, 1H), 4.78 (s, 2H), 2.54 (dd, J = 7.5, 6.2 Hz, 2H), 1.97 – 1.87 (m,
2H), 1.21 (s, 6H); 13C NMR (100 MHz, CDCl3) δ: 198.1, 156.5, 148.3,
136.8, 129.2, 121.0, 110.8, 55.9, 36.0, 35.4, 33.5, 28.1; IR (film) υmax
:
3425, 3043, 2867, 2743, 2213, 2156, 1715, 1678, 1324, 1061, 1048,
936, 834 cm-1.
Synthesis of 2-arylcyclohexanone (±)-15: In an oven-dried round-
bottom flask, under N2 atmosphere, 2-aryl-cyclohexenone 13b (35 mg,
0.16 mmol, 1 equiv.) was taken in methanol (3 mL). To this solution
was added Pd-C (10 mol% w/w) and the reaction mixture was exposed to
1 atm. of hydrogen gas. After completion of the reaction (as judged by
running TLC, 1 h), the reaction mixture was filtered through celite pad.
Finally, the crude products were purified by flash chromatography using
(hexanes:EtOAc = 90:10) to afford product (±)-15.
3',4'-Dimethoxy-5,5-dimethyl-4,5-dihydro-[1,1'-biphenyl]-2(3H)-one
(13f): According to general procedure, compound 13f was obtained as
yellow gel (0.22 mmol scale of reaction, 49.3 mg of product, 86% yield);
Rf = 0.48 (20% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ: 6.90 –
6.85 (m, 3H), 6.68 (d, J = 1.0 Hz, 1H), 3.90 (d, J = 4.0 Hz, 6H), 2.63 (dd,
J = 7.5, 6.2 Hz, 2H), 2.02 – 1.92 (m, 2H), 1.27 (s, 6H); 13C NMR (100
MHz, CDCl3) δ: 198.1, 156.5, 148.7, 148.3, 136.8, 129.2, 121.0, 112.2,
110.8, 55.9, 36.0, 35.4, 33.5, 28.1; IR (film) υmax: 3042, 2954, 2865,
2256, 1765, 1678, 1311, 1046, 953, 825, 765 cm-1; HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C16H21O3 : 261.1485, found: 261.1493.
4,4-Dimethyl-2-(p-tolyl)cyclohexan-1-one (15): Compound (±)-15 was
obtained as yellow gel (0.16 mmol scale of reaction, 34.2 mg of product,
99% yield); Rf = 0.57 (20% EtOAc in hexane); 1H NMR (400 MHz,
CDCl3) δ: 7.16 (d, J = 1.9 Hz, 2H), 7.14 (d, J = 1.9 Hz, 2H), 3.14 (dd, J
= 13.0, 11.9 Hz, 1H), 2.59 – 2.51 (m, 1H), 2.36 (s, 3H), 2.20 (dt, J =
13.4, 2.1 Hz, 1H), 1.86 – 1.79 (m, 2H), 1.68 (s, 2H), 1.15 (s, 3H), 1.03 (s,
3H); 13C NMR (100 MHz, CDCl3) δ: 211.2, 141.3, 136.3, 129.4, 126.5,
54.3, 48.3, 46.5, 40.0, 35.4, 32.2, 25.7; IR (film) υmax: 3043, 2967, 2867,
2663, 2067, 1722, 1486, 1265, 1154, 1045, 935, 867, 724 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C15H21O : 217.1587, found: 217.1577.
2',3'-Dimethoxy-5,5-Dimethyl-4,5-dihydro-[1,1'-biphenyl]-2(3H)-one
(13g): According to general procedure, compound 13g was obtained as
colorless oil (0.22 mmol scale of reaction, 52.1 mg of product, 91%
1
yield); Rf = 0.49 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3)
δ: 7.44 (d, J = 7.9 Hz, 1H), 7.36 – 7.33 (m, 1H), 7.18 (dd, J = 8.2, 2.1
Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 1.76 (s, 2H),
1.28 (s, 6H), 0.89 (d, J = 14.4 Hz, 2H); 13C NMR (100 MHz, CDCl3)
200.1, 159.7, 156.6, 130.3, 129.9, 128.6, 127.1, 120.7, 111.2, 55.4, 51.2,
44.0, 34.2, 28.2; IR (film) υmax: 3018, 2969, 2852, 2235, 2138, 1684,
1409, 1160, 1058, 950, 843, 757cm-1; HRMS (ESI-TOF) m/z: [M+H]+
calcd for C16H21O3 : 261.1485, found: 261.1493.
Synthesis of (±)-ar-macrocarpene [(±)-1]:
In an oven-dried round-bottom flask, compound (±)-15 (30.0 mg, 0.14
mmol, 1.0 equiv) was taken in hydrazine hydrate (2 mL). To this reaction
mixture potassium hydroxide (23 mg, 0.42 mmol; 3.0 equiv) was added
and the reaction mixture was refluxed at 80 °C for 6 h. Upon completion
of the reactions (TLC showed complete consumption of starting
material) the reaction mixture was concentrated in a rotary evaporator
under reduced pressure. Finally, the crude products were purified by
flash chromatography using (100% hexanes) to afford product (±)-ar-
macrocarpene [(±)-1] as colorless oil; Rf = 0.80 (5% EtOAc in hexane)
20.4 mg, 72% yield.
2-(Benzo[d][1,3]dioxol-5-yl)-4,4-Dimethylcyclohex-2-en-1-one (13h):
According to general procedure, compound 13h was obtained as yellow
gel (0.22 mmol scale of reaction, 49.4 mg of product, 92% yield); Rf =
0.50 (20% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ: 6.84 –
6.82 (m, 1H), 6.81 – 6.75 (m, 2H), 6.66 (d, J = 1.0 Hz, 1H), 5.97 (s, 2H),
2.63 (dd, J = 7.4, 6.2 Hz, 2H), 1.96 (td, J = 6.8, 0.9 Hz, 2H), 1.26 (s,
6H); 13C NMR (100 MHz, CDCl3) δ: 197.9, 156.7, 147.2, 147.1, 136.9,
130.3, 122.2, 109.5, 107.9, 101.0, 36.0, 35.3, 33.5, 28.0; IR (film) υmax
:
3023, 2867, 2653, 2342, 2038, 1725, 1685, 1485, 1268, 1046, 936, 854,
827 cm-1; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C15H16O3Na :
267.0992, found: 267.1010.
Luche reduction of enone 13b:

7
To a solution of 13b (35.0 mg, 0.16 mmol, 1.0 equiv.) in methanol was
added CeCl3.7H2O (60.8 mg, 0.16 mmol, 1.0 equiv.). Under ice bath
cooling condition, NaBH4 (6.0 mg, 0.16 mmol, 1.0 equiv.) was added
slowly. Then the reaction mixture was allowed to stir at same
temperature for 1h. Then, the mixture was quenched with water and
extracted with EtOAc (2 x 3mL). The combined organic phase was
washed with brine, dried over Na2SO4 and concentrated under reduced
pressure. Finally the crude product was purified by column
chromatography (90:10 hexanes:EtOAc) to afford the product (±)-12
(31.5 mg, 91 % yield) as a colorless oil.
(R)-4',5,5-Trimethyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-2-ol (+)-12:
Compound (+)-12 was synthesized (yellow gel) as per general reaction
procedure shown above. (0.23 mmol scale of reaction, 44.5 mg of
product, 89% yield); Rf = 0.48 (20% EtOAc in hexane); [α]58928.6= +70.5
(c = 0.5 in CHCl3).
Diastereoselective hydrogenation of compound (±)-12:
Diastereoselective hydrogenation of compound (−)-12:
In an oven-dried round-bottom flask, allyl alcohol (±)-12 (30 mg, 0.138
mmol, 1.0 equiv.) was taken in MeOH (3 mL) under argon atmosphere.
To this reaction Pd-C (10 mol% w/w) was added and it was placed under
1 atm. pressure of hydrogen gas (balloon). Upon completion of the
reaction, (TLC showed complete consumption of (±)-12 after 1 h the
reaction mixture was filtered through celite and concentrated in a rotary
evaporator under reduced pressure. Finally, the crude products were
purified by flash chromatography using (88:12 hexanes:EtOAc) to afford
product (±)-12(30.0 mg, 99 % yield).
Enantioselective reduction of enone 13b:
(1S,2S)-4,4-Dimethyl-2-(p-tolyl)cyclohexan-1-ol [(−)-11]: Compound
(−)-11 was obtained as yellow gel (0.37 mmol scale of reaction, 79.97
mg of product, 99% yield); Rf = 0.50 (20% EtOAc in hexane); H NMR
1
(400 MHz, CDCl3) δ: 7.19 (d, J = 2.7 Hz, 2H), 7.17 (d, J = 4.6 Hz, 2H),
3.98 (q, J = 2.9 Hz, 1H), 2.93 (dt, J = 13.5, 3.0 Hz, 1H), 2.36 (s, 3H),
2.00 (t, J = 13.2 Hz, 1H), 1.86 (dt, J = 10.9, 3.3 Hz, 2H), 1.66 (ddd, J =
13.5, 10.5, 7.8 Hz, 1H), 1.33 (t, J = 3.0 Hz, 1H), 1.22 (dq, J = 13.2, 3.2
Hz, 1H), 1.06 (s, 3H), 1.03 (s, 3H). 13C NMR (100 MHz, CDCl3) δ:
138.5, 137.1, 129.0, 125.4, 67.3, 45.1, 41.5, 31.4, 31.3, 26.1, 21.1, 20.5;
IR (film) υmax: 3365, 3054, 2954, 2783, 2237, 1443, 1361, 1213, 1078,
967, 865, 727 cm-1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C15H22ONa: 241.1563, found: 241.1566. [α]58928.6= −60.0 (c = 1.3 in
MeOH).
2-(p-Tolyl)-cyclohexenone 13b (100.0 mg, 0.46 mmol, 1.0 eq.) was
taken in dry THF (3 mL) and it was placed at −78 ºC. After 15 mins of
stirring at -78 ºC, (S)-(−)-2-Methyl-CBS-oxazaborolidine (46 µL, 0.046
mmol, 0.1 eq.,) was added to the reaction mixture and stirred it for
another 30 min and then BH3.Me2S (26 µL, 0.27 mmol, 0.6 eq.) was
added at -78 ºC. After stirring at same temperature (at −78 ºC) for
another 4 h, the temperature was allowed to warm to rt. After completion
of the reaction (as judged by running TLC, 16 h), most of the organic
volatiles were evaporated under reduced pressure. Finally, the crude
products were purified by flash chromatography using (88:12
hexanes:EtOAc) to afford product (−)-12.
(1R,2R)-4,4-Dimethyl-2-(p-tolyl)cyclohexan-1-ol [(+)-11]: Compound
(+)-11 was synthesized (yellow gel) as per general reaction procedure
shown above. (0.30 mmol scale of reaction, 64.2 mg of product, 98%
yield); Rf = 0.50 (20% EtOAc in hexane); [α]58928.6= +59.5 (c = 0.8 in
MeOH).
Synthesis of xanthate (−)-17:
(S)-4',5,5-Trimethyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-2-ol (−)-(12):
Compound (−)-12 was obtained as yellow gel (0.46 mmol scale of
reaction, 86.5 mg of product, 87% yield); Rf = 0.48 (20% EtOAc in
1
hexane); H NMR (400 MHz, CDCl3) δ: 7.40 – 7.37 (m, 2H), 7.18 (d, J
= 8.0 Hz, 2H), 5.82 (s, 1H), 4.68 (t, J = 4.4 Hz, 1H), 2.37 (s, 3H), 2.01
(dddd, J = 13.8, 11.6, 4.5, 3.4 Hz, 1H), 1.96 – 1.88 (m, 1H), 1.76 – 1.69
(m, 1H), 1.52 (dddd, J = 13.4, 6.6, 3.3, 0.9 Hz, 1H), 1.15 (s, 3H), 1.05 (s,
3H); 13C NMR (100 MHz, CDCl3) δ: 138.0, 137.0, 136.9, 136.6, 129.2,
126.1, 65.7, 32.7, 32.0, 30.2, 28.7, 28.1, 21.1; IR (film) υmax: 3421, 3065,
2987, 2873, 2763, 2254, 2038, 1321, 1165, 1086, 936, 864, 727 cm-1.
Enantiomericexcess of pure compound was determined via HPLC
analysis using a Chiralpak IB column; solvent: hexane/2-propanol =
In an oven dried round bottom flask, (−)-11 (50.0 mg, 0.229 mmol, 1.0
equiv.) was taken in dry THF under N2 atmosphere at room temperature
and NaH (11 mg, 0.275 mmol, 1.2 eq.) was added to the reaction mixture
and stirring was continued for 30 mins. Then CS2 (69µL, 1.14 mmol, 5.0
eq) was added over 15 mins and stirring was continued for another 1.5 h.
Finally, MeI (17 µL, 0.275 mmol, 1.2 eq) was added drop wise to the
reaction mixture. Upon completion of the reaction, (TLC showed
complete consumption of (−)-11 after 6 h) the reaction mixture was
t
95/5; flow rate: 1.00 mL/min; detection: at 254 nm: Rminor = 10.13
t
min, Rmajor = 11.99 min; [α]58928.6= −72.0 (c = 0.8 in CHCl3); (ee =
93%).

8
Tetrahedron
quenched with water (1 mL) and the reaction mixture was concentrated
31.3, 24.7, 22.9, 21.1; IR (film) υmax: 3055, 2964, 2851, 2254, 1321,
1267, 1123, 1076, 957, 842, 823, 735 cm-1; HRMS (ESI-TOF) m/z:
[M]+ calcd for C15H22 : 202.1716, found: 202.1692. Enantiomericexcess
of pure compound was determined via HPLC analysis using a Chiralpak
IB column; solvent: hexane/2-propanol = 100/0; flow rate: 0.06 mL/min;
in a rotary evaporator under reduced pressure. Then, the crude products
were purified by flash chromatography using (hexanes:EtOAc = 98:2) to
afford product (−)-17.
t
t
detection: at 254 nm: Rminor = 05.70 min, Rmajor = 06.05 min;
[α]58928.6= +8.1 (c = 1.2 in n-Hexane); (ee = 86%). [Literature report;
[α]58922= +7.2 (c = 5.1 in n-Hexane) Cool, L. G. Phytochemistry 2005,
66, 249–260].
Total synthesis of (-)-ar-Macrocarpene [ent-1]:
O-((1S,2S)-4,4-Dimethyl-2-(p-tolyl)cyclohexyl)
S-methyl
carbonothioate [(−)-17]: Compound (−)-17 was obtained as yellow gel
(0.229 mmol scale of reaction, 65.7 mg of product, 93% yield); Rf = 0.70
1
(5% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 7.13 (s, 4H), 2.70
(d, J = 1.3 Hz, 1H), 2.39 (d, J = 6.5 Hz, 1H), 2.35 (s, 3H), 1.70 – 1.65
(m, 2H), 1.60 (dt, J = 13.5, 3.8 Hz, 2H), 1.55 (dd, J = 4.8, 2.3 Hz, 2H),
1.30 (s, 3H), 1.03 (s, 3H), 0.97 (s, 3H); 13C NMR (100 MHz, CDCl3 δ
144.9, 135.2, 128.9, 126.7, 121.7, 47.7, 39.5, 38.9, 34.2, 31.2, 29.7, 24.6,
22.8, 14.1; IR (film) υmax , 3043, 2763, 2835, 2267, 2138, 1724, 1688,
1481, 1261, 1048, 936, 727 cm-1; [α]58928.6= −121.0 (c = 0.16 in CHCl3).
(−)-ar-Macrocarpene [ent-1]: (−)-ar-Macrocarpene [ent-1] was obtained
(yellow gel) as per general reaction procedure shown above. (0.10 mmol
scale of reaction, 18.0 mg of product, 89% yield); Rf = 0.8 (5% EtOAc in
hexane); [α]58928.6= −6.9 (c = 0.9 in n-Hexane). [Literature report;
[α]58922= +7.2 (c = 5.1 in n-Hexane) Cool, L. G. Phytochemistry 2005,
66, 249–260].
ACKNOWLEDGEMENT
O-((1R,2R)-4,4-Dimethyl-2-(p-tolyl)cyclohexyl)
S-methyl
V.B. thanks the Science and Engineering Research Board (SERB),
Department of Science and Technology (DST) for a research grant
[CS-021/2014]. A.K. thanks the DST for Inspire fellowship. A.R.
thanks the Council of Scientific and Industrial Research (CSIR) for a
SRF. Facilities from Department of Chemistry, IISER Bhopal is
gratefully acknowledged.
carbonothioate (+)-17: Compound (+)-17 was synthesized (yellow gel)
as per general reaction procedure shown above. (0.20 mmol scale of
reaction, 56.0 mg of product, 91% yield); Rf = 0.70 (5% EtOAc in
hexane); [α]58928.6= +117.0 (c = 0.2 in CHCl3).
Total synthesis of (+)-ar-Macrocarpene [(+)-1]:
§Current Address:
The AB Research Group, Department of Chemistry, Indian Institute
of Science Education and Research Bhopal, Bhopal Bypass Road,
Bhopal - 462 066, India.
REFERENCES AND NOTES
In an oven-dried round-bottm flask, the xanthate (−)-17 (35.0 mg, 0.113
mmol, 1.0 equiv.) was taken in dry benzene (1.5 mL) and was purged for
15 mins under argon. Then the reaction mixture was immerged in a
preheated oil bath at 80 °C. After stirring at 80 °C for 15 minutes, a
mixture of n-Bu3SnH (54.9 mg, 0.204 mmol, 1.8 equiv.) and AIBN (4.6
mg, 0.028 mmol, 0.25 equiv.) in benzene (0.5 mL) was added slowly
over 15 minutes and the stirring was continued for 6 h. Upon completion
of the reaction, (TLC showed complete consumption of (−)-17 after 6 h)
the reaction mixture was concentrated in a rotary evaporator under
reduced pressure. The crude material was purified through column
chromatography by using petroleum ether as eluents to afford (+)-ar-
macrocarpene [(+)-1].
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1526 b) Gupta, P.; Phulara, S. C. J. App. Microbiol. 119, 2015, 605-619.
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249-260.
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Gershenzon, J.; Degenhardt, J. J. Bio. Chem. 2008, 30, 20779-20788. (b)
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Majapolene B acetate (4): Blunt, J. W.; Copp, B. R.; Hu, W.-P.; Munro,
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(+)-ar-Macrocarpene [(+)-1]: (+)-ar-Macrocarpene [(+)-1] was
obtained as yellow gel (0.113 mmol scale of reaction, 16.4 mg of
product, 72% yield); Rf = 0.8 (5% EtOAc in hexane); 1H NMR (400
MHz, CDCl3) δ: 7.23 (s, 4H), 2.81 (tt, J = 12.5, 3.5 Hz, 1H), 2.45 (s,
3H), 2.00 (ddt, J = 12.8, 3.4, 1.7 Hz, 1H), 1.83 – 1.76 (m, 1H), 1.75 –
1.64 (m, 2H), 1.56 (dd, J = 13.1, 3.2 Hz, 1H), 1.48 – 1.39 (m, 2H), 1.32
(td, J = 13.2, 4.6 Hz, 1H), 1.14 (s, 3H), 1.09 (s, 3H). 13C NMR (100
MHz, CDCl3) δ: 145.0, 135.2, 129.1, 126.8, 47.8, 39.7, 39.0, 34.3, 33.6,
6. For isolation of halogenated sesquiterpenes, see; (a) Wang, B.-G.;
Gloer, J. B.; Ji, N.-Y.; Zhao, J.-C. Chem. Rev. 2013, 113, 3632-3685. (b)
Fraga, B. M. Nat. Prod. Rep., 2006, 23, 943-972.

9
7. (a) Mathouet, H.; Elomri, A.; Lameiras, P.; Daïch, A.; Vérité, P.
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8. (a) Mao, S.-C.; Guo, Y.-W. J. Nat. Prod. 2006, 69, 1209-1211. (b) Yu,
X.-Q.; He, W.-F.; Liu, D.-Q.; Feng, M.-T.; Fang, Y.; Wang, B.; Feng, L.-
H.; Guo, Y.-W.; Mao, S.-C. Phytochemistry 2014, 103, 162-170. (c) Our
synthesis of (±)-lauromakurene B, see; Das, M. K.; Dinda, B. K.; Bisai,
V. Tetrahedron Lett. 2019, 60, 2039-2042.
9. (a) Surup, F.; Thongbai, B.; Kuhnert, E.; Sudarman, E.; Hyde, K. D.;
Stadler, M. J. Nat. Prod. 2015, 78, 934-938. (b) Mao, S.-C.; Guo, Y.-W.
Chin. Tradit. Herb. Drugs 2004, 35, 8-17. (c) Our synthesis of (±)-
isolaurene, see; Niyogi, S.; Khatua, A.; Bisai, V. Tetrahedron Lett. 2019,
60, 150941.
10. (a) Fraga, B. M. Nat. Prod. Rep. 2013, 30, 1226-1264. (b) Hill, R. A.;
Sutherland, A. Nat. Prod. Rep. 2017, 34, 1180-1184.
11. Srikrishna, A.; Beeraiah, B. Synth. Commun. 2007, 37, 2855-2860.
12. For total synthesis of (+)-ar-macrocarpene (1) from our group, see;
Khatua, A.; Niyogi, S.; Bisai, V. Org. Biomol. Chem. 2019, 17, 7140-
7143.
13. (a) Corey, E. J.; Bakshi, R.; Shibata, S. J. Am. Chem. Soc. 1987, 109,
5551-5553. (b) Corey, E. J.; Bakshi, R.; Shibata, S.; Chen, C.-P.; Singh,
V. K. J. Am. Chem. Soc. 1987, 109, 7925-7926. (c) Corey, E. J.; Link, J.
O. J. Am. Chem. Soc. 1992, 114, 1906-1908.
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Fuchs, P. L. J. Org. Chem. 1976, 41, 2935-2937.
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Soc. 2009, 131, 11187-11194.
18. The enantioselectivity of 1 was determined by running HPLC using
IB column with 100% n-hexane with flow rate of 0.6 mL/min (see the
Supporting Information for details). The absolute stereochemistry was
assigned by the analogy, see; Majetich, G.; Zou, G.; Grove, J. Org. Lett.
2008, 10, 85-87.
19. The enantioselectivity of 1 found to be 86% ee based on HPLC
analysis. The diastereomeric mixture of hydroxyl compound (−)-11 (93%
ee, dr = 10.3:1) was converted [via xanthate (−)-17] to single enantiomer,
1, therefore, a reduction of enantioselectivity of 1 was observed from
93% ee to 86% ee.

Vishnumaya Bisai, Ph.D.
23rd November, 2019
Highlights for the publication in Tetrahedron
Manuscript Title: Catalytic Asymmetric Total Syntheses of Sesquiterpenoids, (+)- and ()-ar-
Macrocarpene
Authors: Arindam Khatua,a Avishek Roy,a and Vishnumaya Bisai*a,b,c
Dear Editor,
Kindly see following highlights for this manuscript:
(a) Total syntheses of Sesquiterpenoids, (+)- and ()-ar-macrocarpene is reported.
(b) A key catalytic enantioselective Corey-Bakshi-Shibata reduction of 2-arylenone is explored.
(c) Highly diastereoselective hydrogenation of allylalcohol sets stereochemistry at benzylic
position.
(d) Sesquiterpenes, (+)- and ()-ar-Macrocarpene were synthesized only in 6 steps with ~60-
61% overall yield from commercially available enone.
Thanking you.
With best regards,
(Vishnumaya Bisai)